The Los Angeles Center of the Multicenter AIDS Cohort Study (MACS) has followed 93 percent of the men who were seropositive at entry into the cohort or subsequently seroconverted since 1984 and 95 percent of the seronegative men who engage in high-risk activities with many partners. The MACS has published 678 papers on the epidemiologic, virologic, immunologic, genetic, behavioral, clinical, and neuropsychologic aspects of HIV/AIDS since 1984. This is a follow-up of the surviving men in the Los Angeles Center from 1999-2004. They include those who were seropositive at entry into the cohort, those who have seroconverted since entry into the cohort, seronegative men with many high-risk exposures, and a sample of seronegative men followed for quality control of technical procedures. The objectives of the proposal are: 1) to determine the long-term effectiveness of highly active retroviral therapy and newer therapies, 2) to determine the spectrum of individual responses to therapy, 3) to characterize the virologic parameters, immune responses and host genetic factors in progressors and non- progressors, 4) to characterize the nature of resistance to infection in HIV-1 seronegative men with many exposures to HIV-1, 5) to increase knowledge and understanding of prognostic markers, and 6) to further elucidate the epidemiology and pathogenesis of HIV-1 related malignancies. The men will continue to be followed semiannually for changes in behavior, health status, AIDS- defining and AIDS-related conditions, neuropsychologic performance, drug usage (including antiretroviral drugs), health services access and use, CD4+ and CD8+ levels, HIV-1 RNA levels, and CD38+CD8+ cell levels and expression. Seronegative men will be followed for seroconversion. Biopsies will continue to be sought and autopsies performed according to the MACS protocol. The UCLA Center will continue to collaborate with the MACS Executive Committee, the designated MACS HIV pathogenesis laboratories, and other investigations approved by the MACS Executive Committee. These continued studies should provide vital information on treatment effectiveness and on basic biologic mechanisms essential for development of more effective treatments and for development of effective therapeutic and preventive vaccines.